title: Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice.
abstract: This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST) or forced-swimming (FST) depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg), fluoxetine (20 mg/kg) and bupropion (30 mg/kg) significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg), indomethacin (10 mg/kg) and celecoxib (30 mg/kg) markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg) or pregabalin (30 mg/kg) significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg) did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg) was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg), and depression behaviour was prevented by celecoxib (30 mg/kg). The co-treatment with bupropion and celecoxib (3 mg/kg each) significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1β, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and anti-inflammatory agents bupropion and celecoxib might represent an attractive therapeutic strategy for depression.
authors.affiliation: Postgraduate Program in Medicine and Health Sciencies, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre/RS, Brazil.
authors.forename: Izaque S
authors.initials: IS
authors.lastname: Maciel
authors.forename: Rodrigo B M
authors.initials: RB
authors.lastname: Silva
authors.forename: Fernanda B
authors.initials: FB
authors.lastname: Morrone
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.forename: Maria M
authors.initials: MM
authors.lastname: Campos
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016642:Bupropion / Q000494:pharmacology* / Q000627:therapeutic use; D000068579:Celecoxib; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003863:Depression / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D004177:Dipyrone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000150:complications; D005620:Freund's Adjuvant / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects; D000069583:Pregabalin; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D011720:Pyrazoles; D013449:Sulfonamides; D016642:Bupropion; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D004177:Dipyrone; D005620:Freund's Adjuvant; D051546:Cyclooxygenase 2; D000068579:Celecoxib